This invention relates to pharmaceutical compositions for oral administration comprising a drug compound, chitosan or a derivative thereof or a salt of chitosan or a salt of a derivative of chitosan and an organic acid.
The oral route is the preferred means by which drugs are administered to humans and animals due to its convenience, simplicity and acceptability to patients. Most conventional drugs are well absorbed from the intestines, usually by a process of passive absorption, although certain compounds are taken up by more specific means such as facilitated or active transport. Small polar molecules often display poor or erratic absorption when dosed orally. Polypeptide, polysaccharide and protein drugs cannot generally be given orally for reasons of hydrophilicity, high molecular weight and susceptibility to degradation by the acidic and enzymatic environment of the gastrointestinal tract. As a consequence, with few exceptions, negligible amounts of peptide and protein compounds are absorbed into the systemic circulation when administered by the oral route. The absolute oral bioavailability of such compounds (the percentage absorbed compared to the same dose given as an intravenous injection) is generally less than 1%. A notable exception is cyclosporin, which is a non-polar peptide compound with a partition coefficient (octanol/water) exceeding 1000.
There has been intense interest in developing novel delivery strategies to circumvent the obstacles to the delivery of peptide and protein drugs by the oral route. One possible strategy is to formulate the peptide/protein drug with a compound that enhances drug uptake across the intestinal mucosal wall.
One such compound is chitosan. Chitosan is a bioadhesive polymer derived from the acetylation of chitin and comprises glucosamine and N-acetyl glucosamine units.
The use of chitosan to increase transmucosal absorption of drug compounds is described in WO90/09780. Luessen et al, (J. Control. Rel., 45, 15-23, 1997) reported that chitosan glutamate, as an aqueous solution at pH 5.6, increased the transport of peptide compounds across Caco-2 cell monolayers and isolated rat intestinal loop. Thanou et al (Pharm. Res., 18, 823-828, 2001) investigated intestinal absorption of the peptide compound, octreotide, in pigs. Administration of an aqueous solution containing chitosan hydrochloride at pH 5.5 or trimethyl chitosan chloride at pH 7.4 led to substantial increases in bioavailability compared to a solution of octreotide alone.
The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
The studies mentioned above used chitosan in the form of an aqueous solution. This has a number of disadvantages for oral peptide/protein administration. In particular, the peptide/protein will come into direct contact with gastric juice, with potentially serious consequences. The acid and enzyme (pepsin) content of gastric juice can result in significant degradation and loss of activity of the peptide/protein compound. In addition, many peptide/protein compounds do not have good long-term stability when prepared as aqueous solutions.
There is a need to provide a means for oral administration of drug compounds that are often not successfully administered by the oral route. Such drugs include small polar molecules, peptides, proteins and polysaccharides. In particular, there is a need to provide a composition containing these drug compounds in the form of a tablet or capsule which ensures good stability, provides effective oral absorption and allows for the possibility of acid-resistant coatings to be applied to protect the drug compound from the gastric environment.
The present invention provides a composition suitable for oral administration that addresses this need.